CN106573145A - Selective nerve stimulation using presynaptic terminal depletion block - Google Patents

Abstract

An example of a system may include a stimulator and at least one controller. The stimulator may be configured to deliver nerve stimulation to capture a first set of axons in a nerve and to deliver depletion block stimulation to capture a second set of axons in the nerve, where the second set is a subset of the first. The depletion block stimulation may include a series of pulses at a depletion pulse frequency within a range between about 100 Hz to about 1 kHz, and the nerve stimulation may include a series of pulses at a stimulation pulse frequency within a range of about 0.25 Hz to about 50 Hz. At least a portion of the nerve stimulation and at least a portion of the depletion block stimulation may be delivered to be effective in providing a nerve block while delivering nerve stimulation.

Description

The selective nerve stimulation of retardance is exhausted using presynaptic ending

Claim priority

The U.S. Provisional Patent Application sequence that the application requires to be submitted on January 17th, 2014 according to 35U.S.C. § 119 (e) The rights and interests of the priority of row number 61/928,732, here is integrally incorporated by quoting with it.

Cross reference to related applications

Following commonly assigned U.S. Patent application is related, is all submitted to the application same date, and is all existed This is integrally incorporated by quoting with it：“Systems and Methods for Selective Stimulation of Nerve Fibers in Carotid Sinus, " serial number 61/928707 submits on January 17th, 2014；“Systems And Methods for Delivering Pulmonary Therapy " serial numbers 61/928714 were carried on January 17th, 2014 Hand over；" Depletion Block To Block Nerve Communication, " serial number 61/928725 was in 2014 1 The moon 17 was submitted to.

Technical field

This document relates generally to armarium, more particularly, to the system for delivery of selective nerve stimulation, if Standby and method.

Background technology

Nerve stimulation is proposed as the therapy for some diseases.For example, nerve stimulation can be delivered to adjust Section autonomic nervous system, it can be referred to as autonomic nerve modulation therapy (AMT).The example of AMT is included for breathing problem Therapy such as sleep disordered breathing, controlling of blood pressure are such as declined with treating hypertension, cardiac rhythm management, myocardial infarction and ischemia, heart Exhaust (HF) and modulation cholinergic antiinflammatory path.For example, treat epilepsy, depression, pain, migraine, eating disorders, obesity and Dyskinetic therapy can include vagal stimulation.

Some neural targets be with it is different types of can innervation body different piece nerve fiber complexity Structure.The indiscriminate stimulation of this labyrinth may provide intended effect, it is also possible to providing undesirable secondary work With.For example, neck vagus nerve is the nerve of the combination with various sizes of fiber.Recurrent laryngeal nerve is from neck vagus nerve branch and refreshing Muscle around Jing dominations throat.Vagus nerve continues to drop to laryngeal nerve branch lower section with the other parts of innervation body Including heart, lung, liver, stomach, intestinal, bladder and kidney.Have been proposed that the vagal therapy of stimulation neck, such as heart failure therapy. It may be desirable to stimulating neck vagus nerve by this way, that is, activate the fiber of innervation heart and do not activate neck vagus nerve Some other fibers, with avoid it is undesired to stimulate physiological responses.

The content of the invention

The various embodiments of description can be related to deliver nerve stimulation and exhaust retardance (depletion block) The method and system of stimulation.Nerve stimulation can be applicable to cause the action potential in some aixs cylinders, and exhaust retardance stimulation can It is applied to block across the synaptic space communication of action potential at least some in these aixs cylinders.

One example of system can include stimulator and at least one controller.Stimulator can be configured to delivering god The first aixs cylinder during Jing stimulates to capture nerve exhausts the second aixs cylinder blocked in stimulating to capture nerve with delivering, wherein Second group of aixs cylinder is the subset of first group of aixs cylinder.Exhausting retardance stimulation can be included in about 100Hz to the scope about between 1KHz The company exhausted at pulse frequency of interior (such as 100Hz to 1000Hz or the frequency near the scope exhaust retardance to provide) Series impulse, and nerve stimulation may include a succession of arteries and veins at the boost pulse frequency in the range of about 0.25Hz to about 50Hz Punching.At least one controller can be configured to be communicated with stimulator and control exhausts retardance and stimulates and nerve thorn Swash.At least a portion nerve stimulation can be delivered and at least a portion exhausts retardance and stimulates with effectively in the same of delivering nerve stimulation When nerve block is provided.

The example of method may include to stimulate the nerve delivering with multiple aixs cylinders.Delivering stimulation can include that delivering is matched somebody with somebody The nerve stimulation of first group of aixs cylinder being set in capture nerve.Delivering nerve stimulation can include delivering at boost pulse frequency A succession of electric pulse, wherein the boost pulse frequency is between the scope of about 0.25Hz and about 50Hz, wherein being delivered Nerve stimulation can induce action potential in first group of aixs cylinder.Delivering stimulation can be configured to capture nerve including delivering In second group of aixs cylinder presynaptic exhaust retardance stimulate.Second group can be first group of subset.The delivering presynaptic exhausts resistance Stagnant stimulation can include that delivering exhausts a succession of electric pulse at pulse frequency.Exhausting pulse frequency can be in about 100Hz to about Between 1kHz.Delivering at least a portion nerve stimulation and at least a portion exhaust retardance to stimulate with effectively in delivering Nerve block is provided while nerve stimulation.

Present invention is the general introduction of some teachings of the application and processes this with being not intended to exclusiveness or exhaustive Bright theme.Describing in detail and the further detail below with regard to present subject matter is being found in appended claim.For reading The following detailed description and check for the those skilled in the art for constituting part thereof of accompanying drawing with understanding, the disclosure its Its aspect will be apparent, and wherein the detailed description and the accompanying drawings are not taken in a limiting sense.The scope of the present disclosure by Claims and its legal equivalents are limited.

Description of the drawings

By way of example various embodiments are shown in each figure of accompanying drawing.Such embodiment is used to demonstrate, not purport Becoming the exhaustive or exclusiveness embodiment of present subject matter.

Fig. 1 illustrates the neural activity at the synapse between neural and another film.

Fig. 2 is illustrated for observing the experimental provision that presynaptic ending exhausts retardance.

Fig. 3 illustrate when stimulate change to 200Hz from 20Hz when between stimulus signal and the ENG that recorded and EMG signal Observed relation, and also including for exhaust presynaptic ending and retardance synapse joint (synaptic junction) The observed time.

Fig. 4 illustrate when stimulate change to 20Hz from 200Hz when between stimulus signal and the ENG that recorded and EMG signal Relation.

Fig. 5 A and 5B illustrate response of the neuromuscular junction to different stimulated frequency.

Fig. 6 illustrates vagal some branches of cervical region.

Fig. 7 is illustrated from the left side of figure VST intensity cumulative to the right, and also illustrates that the various physiological responses caused to VST Intensity threshold.

Fig. 8 is illustrated from the left side of figure VST intensity cumulative to the right, and further illustrates that initiation is undesirable to VST's The intensity threshold of physiological responses, it is used to define the upper limit of VST intensity, and causes the another of another physiological responses to VST One intensity threshold.

Fig. 9 A-9C go forward side by side one using the schematic representations of the different stimulated threshold value of the different fiber types in complicated nerve 928 Walk and exhaust the various combination explanation selective stimulating that retardance stimulates using nerve stimulation and presynaptic ending.

Figure 10 illustrates first group of aixs cylinder 1030 in the nerve captured by nerve stimulation and stimulates capture by retardance is exhausted Second group of aixs cylinder 1031, wherein, second group of aixs cylinder is the subset of first group of aixs cylinder.

Figure 11 A-11M are illustrated and are used for exhausting the one of the electrode configuration that retardance stimulates delivery of selective nerve stimulation A little examples.

Figure 12 illustrates by way of example, and not limitation nerve stimulation and exhausts the concurrently delivering that retardance stimulates (concurrent delivery)。

Figure 13 illustrates by way of example, and not limitation concurrent nerve stimulation and exhausts the intermittent delivery that retardance stimulates.

Figure 14 illustrates by way of example, and not limitation an example of selectivity nerve fiber stimulation system.

Figure 15 illustrates by way of example, and not limitation an example of selectivity nerve fiber stimulation system.

Figure 16 illustrates the expression of intermittent nerve stimulation (INS) by way of example.

Figure 17 illustrates the memorizer in the controller that may be incorporated into Figure 14 or Figure 15 according to various embodiments, and it can So that including instruction, the instruction can be operated by boost control circuit, for control titration procedure (up-titration is raised routine)。

Figure 18 illustrates an embodiment party of the treatment titration module for the part that can be titration control module in Figure 15 Case.

Figure 19 illustrates an embodiment for searching the program of threshold value for each electrode configuration.

Figure 21-30 illustrates by way of example, and not limitation some selectivitys that can be performed using retardance stimulation is exhausted Fiber stimulating course.

Figure 31-34 illustrates the system implementation plan for being adapted to provide for vagal stimulation.

Describe in detail

The reference described in detail below of present subject matter shows by way of example the tool that can put into practice present subject matter The accompanying drawing of body aspect and embodiment.Fully describe in detail these embodiments to enable those skilled in the art to reality Trample present subject matter.Other embodiments can be utilized on the premise of the scope without departing from present subject matter, and can be carried out Structure, logical sum electricity changes." one " for quoting in the disclosure, " one " or " various " embodiment are not necessarily same reality Scheme is applied, and such reference considers more than one embodiment.Therefore, detailed description below, is not to be seen as tool Restricted meaning, and scope is defined only by the following claims, together with the legal equivalents of these claims issues Four corner.

Nerve fiber, also referred to as aixs cylinder, are the projections of neurocyte.Nerve fiber connects neurocyte at synapse To another neurocyte or it is connected to muscle cell or glandular cell.Synapse is to allow neurocyte to transmit electric or chemical signal to arrive The structure of other cells.Nerve fiber includes A fibers, fiber B and fiber C.A fibers are maximums and generally work as stimulation amplitude It is captured first during increase.A fibers can be the sensory fiber (incoming) or motor fiber (spreading out of) of innervation muscular tissue. For example, the vagal stimulation in neck area can excite the laryngeal muscles fiber for causing laryngeal activity, and it can serve as fan and walks The labelling of the capture of nerve.Fiber B is less and next captured when current amplitude is increased.These are all typically to spread out of Parasympathetic nervouss and sympathetic fiber.These fiber Bs can be the target spot of autonomic nerve stimulation treatment.Fiber C it is minimum and Associate with pain and other sensory informations.

Have been observed that thicker nerve fiber is generally first activated than relatively thin nerve fiber.Thick nerve fiber is being gone There is longer myelin part, so as to they experience bigger electric field change between the Ranvier nodes of polarization.At present evidence is recognized For vagus nerve includes the fiber type and size shown in table 1, and is further contemplated that most of fiber is fiber C.

Form 1

Vagus nerve fibers

Some autonomous stimulation therapies proposed attempt to be walked by being up to tolerable titration amplitude capture fan as much as possible Nerve fiber in nerve.Generally speaking, vagal stimulation can first capture A motions and big Sensory nerve fibre, Ran Hou little Feel and B parasympathetic fibers.This is sequentially general order, because the fiber closer to electrode experiences higher electricity , and first activate than distant fiber, and further the size of these fiber types is overlapped.Heart rate is driven to decline Fiber be that minimum B spreads out of parasympathetic fibers.These B spread out of parasympathetic fibers be it is minimum have myelin fiber, Because fiber C is without myelin.The nerve stimulation that heart rate is responded is caused to represent that B spreads out of parasympathetic fibers and is captured, and its He is also captured at larger fiber type.

Fig. 1 illustrates the neural activity at the synapse between neural and another film.Action potential is electric along neural axon 100 Propagate until it reaches the teleneuron that can be referred to as presynaptic ending 101.Presynaptic ending and the postsynaptic membrane of target cell 102 communications.Target cell can be another kind of nerve or muscle or body of gland.The film of presynaptic ending and target cell to film connects quilt Referred to as synapse 103.A type of synapse is electrical synapse joint, and wherein presynaptic ending is used through a cell to the next one The ion or small molecule of the passage of cell and postsynaptic membrane telecommunication.Another type of synapse is chemical synapse joint (synaptic junction), wherein neurotransmitter are used to be transmitted between cell.Synapse proparea 101 have it is substantial amounts of containing The synaptic vesicle 104 of neurotransmitter chemicals 105.The action potential for traveling to presynaptic ending 101 drives presynaptic ending In chemical reaction, its synaptic vesicle release neurotransmitters from tip is to cell outer void.The cell outer void can be by Referred to as synaptic space 106.Synaptic space of the neurotransmitter between presynaptic and postsynaptic tip.Neurotransmitter starts the postsynaptic Reaction chain in the acceptor 10 7 of film 102 (another neuronal cell) or muscle cell (neuromuscular junction), its triggering postsynaptic Action potential in neuron excites (firing) or triggers muscle contraction if synapse is terminated in neuromuscular junction. For example, when target cell is muscle and synapse is neuromuscular junction, neurotransmitter acetylcholine (Ach) causes target muscle cell Rapid desufflation.In neuromuscular junction, action potential travels to neuromuscular synapse joint, so as to cause calcium ion to flow through Valtage-gated calcium channel 108, it discharges Ach to cell outer void from presynaptic ending.Postsynaptic in the film of target muscle cell Receptor receives the Ach.Presynaptic ending has neurotransmitter re-uptake pump 109, and it uses the synaptic vesicle of neurotransmitter to supplement Presynaptic ending.

Present inventors have observed that, seem to require that in nerve between action potential across the Continued communication of synaptic space 106 Minimum time amount, it has been observed that if presynaptic action potential reach it is closer to each other, the postsynaptic receptor not trigger action electricity Position.Higher stimulus frequency will produce more boost pulses within preset time, it is possible to produce in this section of time intrinsic nerve Raw more corresponding action potentials.For example, nerve stimulation signal can be in the range of about 0.25Hz to 50Hz, it is also possible to In the range of about 2Hz to about 20Hz, or can be about 20Hz.Under higher frequency (e.g., from about 100Hz to about 1kHz), Ke Yiguan Observe presynaptic ending cannot across synaptic space communication, even if action potential continues to propagate through aixs cylinder.Presynaptic ending this Planting to communicate can be referred to as exhausting retardance.Compare meeting block action potentials along nerve for obtaining the frequency for exhausting retardance High frequency (being more than 1KHz) the AC nerve blocks of propagation are low.Under the frequency higher than 1KHz, for example, stimulate blocking nerves conduction action Current potential.In contrast, exhaust to be arrested under the frequency less than 1kHz and deliver, therefore action potential will not be stopped along neural propagation To presynaptic ending, but presynaptic ending is exhausted, therefore it is no longer able to across synaptic space with another cell by body communication.

Fig. 2 is illustrated for observing the experimental provision 210 that presynaptic ending exhausts retardance.Neck vagus nerve 211 turns to breast Wide branch 212 and recurrent laryngeal nerve 213.Shown experimental provision is used for using the current source 214 and screw electrode in bipole arrangement 215 stimulate neck vagus nerve 213, branch into larynx using the monitoring neck of electro-neurogram (ENG) monitor 216 vagus nerve 211 and return god Neural activity before Jing branches 213 and thorax branch 212, and monitor laryngeal muscles 217 using electromyogram (EMG) monitor 218 Vibration.The device be used for observation from exhaust retardance stimulate action potential still sensed by ENG, but laryngeal vibration not by EMG 218 is sensed.It was therefore concluded that, this exhausts retardance stimulates what retardance presynaptic ending communicated across synaptic space Ability.

Fig. 3 is illustrated when stimulation changes to 200Hz from 20Hz, between stimulus signal and the ENG for being recorded and EMG signal It was observed that relation, and also including exhaust presynaptic ending and retardance synapse joint observe time.Stimulate in 20Hz Period, ENG and EMG signal all follow stimulus signal.Peak reflection stimulus artifact (artifact) in ENG and EMG signal.So And, during 200Hz stimulates, ENG responses are yet suffered from after stimulus signal, but EMG signal rings in the starting of about 100ms Should rear prompt resolution.Stimulation was changed to after the short transition phase after 200Hz, and the artefact only from charge balance is occurred in In EMG waveforms.Therefore, the aixs cylinder in nerve continues active by propagating action potential, but across synaptic space communication prominent Tip has exhausted it and has reduced or stop after the ability of synaptic space communication before touching.As illustrated, the synapse joint retardance is sent out Life very fast (for example, 50 to the 100ms after 200Hz signals are applied), once exhaust presynaptic ending in presynaptic ending Occur by propagation pulse is received during the ability of communication.Seem to recover neurotransmitter and/or calcium in presynaptic ending Physiology reuptake process can not catch up with the transmission of neurotransmitter caused by 200Hz stimulates.

Fig. 4 is illustrated when stimulation changes to 20Hz from 200Hz, between stimulus signal and the ENG for being recorded and EMG signal Relation.There is the retardance of synapse joint when stimulating and being delivered under 200Hz.During this period, ENG after stimulus artifact signal still Exist but EMG responses are not present.This shows that stimulation is just capturing nerve and causing action potential to propagate through aixs cylinder.In stimulation Each pulse causes the corresponding action potential in nerve fiber.However, because causing the presynaptic ending that synapse joint blocks Exhaust, laryngeal muscles is not upset.200 action potentials per second exhaust the ability that presynaptic ending communicates across synaptic space.But, When stimulation changes to 20Hz from 200Hz, ENG responses are still present after a stimulation pulse, because each pulse in stimulating Cause the corresponding action potential in nerve fiber.The short transition phase after stimulus frequency changes into 20Hz is after After boost pulse, EMG occurs again.Presynaptic ending is not exhausted across the ability that synaptic space communicates by 20 pulses per second. Therefore, as illustrated, synapse joint retardance can very rapidly remove (for example, signal from 200Hz change to 20Hz signals it 50ms to 100ms afterwards), when this is considered as the physiological responses for reflecting the neurotransmitter and/or calcium recovered in presynaptic ending Between.

As shown in table 2, it can be observed that some frequencies more quickly beat the consumption of opening/closing synapse joint than other frequencies Retardance to the greatest extent.The frequency of as shown by data, greater than about 200Hz is provided and exhausts retardance soon, and about 100Hz is to the frequency about between 150Hz There is provided and slower exhaust retardance.Frequency less than 100Hz is tended not to effectively provide and exhausts retardance, because these frequencies do not surpass Cross presynaptic ending and recover its ability across synaptic space from presynaptic ending communication to the ability of target cell.Connect in neuromuscular In head, for example, the less than about frequency of 100Hz causes tetanic contraction；About 100Hz is to the frequency about between 150Hz at about 10 seconds to 4 90% is caused to exhaust retardance in second；Frequency about between 200Hz to 1000Hz causes 90% to exhaust retardance；With more than 1KHz Frequency initially enter nerve block, wherein it is described stimulate prevent action potential along neural propagation.

Table 2

Random research；N=8 (100Hz：N=5), data are from 2*N=1

Fig. 5 A show response of the neuromuscular junction to different stimulated frequency.Neuromuscular junction is that a kind of synapse connects Head, in this place nerve in aixs cylinder communicate with muscle.The thorn of the aixs cylinder in the range of usually less than 100Hz (such as about 50Hz) Swashing can cause the tetanic contraction of muscle.Finally, muscle understands fatigue and no longer responds extra stimulation.In about 100Hz to big Presynaptic ending exhausts its ability across synaptic space communication under stimulus frequency in the range of about 1kHz.Stimulus signal this Frequency physiological system trigger muscle contraction ability outside because the frequency may cause action potential to reach must pass than nerve Matter and/or calcium are added for the action potential in subsequent stimulation faster.Observed retardance is attributed to exhausting for joint Rather than the fatigue of muscle.Therefore, the benefit for exhausting retardance for being applied to neuromuscular junction is to exhaust retardance to be not result in flesh Meat fatigue or tetanic contraction.It is Rapid reversible that neuromuscular exhausts retardance by stopping stimulating.

It should be noted that Fig. 5 A are a simple examples of frequency range, and these scopes can be directed to it is different Using and change.Fig. 5 B provide another example of neuromuscular junction to the response of different stimulated frequency.Fig. 5 B illustrate sharp Live and exhaust the transition period T1 between block scope.Transition period T1 can depend on the person of sending and synapse end-organ, and can With in the range of about 70 to 130Hz.Fig. 5 B also illustrate that can provide combination exhaust with conduction block exhaust retardance and Transition period T2 between conduction block scope.

It has been provided below and has exhausted retardance, some features exhausted with conduction block and high frequency kHz conduction blocks of combination. For example, with relatively low frequency so as to relatively low power requirement exhaust retardance with relatively fast retardance (<It is 100ms) and relative Fast recovery (<100ms more than 50% and 10 seconds 100%).For example, exhausting for combination can with conduction block (e.g., from about 1kHz) To block very much slowfiber soon due to conduction block, can be started with high kHz frequencies, be then reduced in relatively low frequency It is lower to keep retardance, slower fiber can be blocked being less than in 7ms, and can have more extensive faster than upper frequency kHz retardances It is multiple.For example, high frequency kHz conduction blocks are fast (for example：Open：<7ms is closed：<10ms), but due to higher frequency and current requirements And more energy-intensive.

For example, the 1kHz observation KHz conduction blocks that can be illustrated with the lower limit of about 1kHz to 5kHz rather than simply. Additionally, the upper limit for exhausting retardance can be about 2kHz, rather than the 1kHz for simply illustrating.Additionally, stimulating from exhausting transition Frequency to conduction depends on nerve fiber and soleplate.Fast alpha fibre has higher conduction and excitation rate (firing ), therefore they not necessarily block at 1 khz, and slower fiber will hinder under relatively low frequency (such as 600Hz) rate It is stagnant.Accordingly, it is possible to there is such nerve stimulation frequency band, most of fibers can be activated in the frequency band, it is understood that there may be this Sample exhausts retardance frequency band, for its most fiber with depleted, and can there may be such kHz conduction blocks frequency Band, for its most of fiber has blocked action potential.For example, the nerve stimulation frequency band can be extended to about 50Hz, the retardance frequency band that exhausts can extend in about 100Hz to about between 700Hz, and kHz conduction blocks frequency band can be from about 5kHz extends to 100kHz.Transition frequency is there may be among frequency bands, and e.g., from about 50Hz is to about between 100Hz or e.g., from about Transition between 70Hz to 130Hz, and in about 700Hz to another kind of transition about between 5kHz.Nerve is to stimulus frequency Response seems to depend on the person of sending and synapse end-organ.Therefore, different types of fiber can be to the frequency in transition frequency Differently respond.For example, a kind of frequency can cause the activation or nerve stimulation of some fibre, and cause other fibers Exhaust retardance.Stimulating can be limited to special fiber by the position of the diameter of fiber or origin or electrode.For example, it may be possible to send out Frequency that retardance stimulates now is exhausted being transferred into and out being made a distinction between nerve fiber, or pass different types of nerve is sent Make a distinction between the different fibers of matter.This frequency for exhausting retardance and activating/stimulate can be provided can be in transitional region Middle discovery, but it is also possible to find in one of frequency band, is such as exhausting in retardance frequency band.

Although the response to different frequency can be simultaneously expected to change as application is different, but exhaust retardance for delivering Stimulus parameter expection can reasonably energy consumption cost be used for current equipment.Shown in form wherein in 300 μ s pulse width Degree is lower to be provided in the research for stimulating, and A fibers are blocked under 2mA, 200Hz, and are still excited in 5mA, and under 20Hz the heart is ordered about The fiber B that rate declines.A- fibers are responsible for the larynx motor fiber recorded by EMG.Little secondary friendship with higher activation threshold Sense nerve spreads out of the Rate control that B- fibers are generally responsible in sinuatrial node.This example shows that NMJ blocks, as via electricity thorn Sharp activation, is classified according to the size of the fiber aixs cylinder of targeting.

As shown in table 2, the speed for exhausting retardance depends on the frequency for stimulating, wherein in about 100Hz to about 1kHz models Higher frequency in enclosing more quickly provides neurotransmitter retardance than lower frequency within the range.According to some embodiment party Case, can implement to exhaust retardance by such process, and (for example, about 200Hz is extremely in relatively high frequency for the process Start under 400Hz) and exhaust retardance to realize rapidly depleting (e.g., from about 50ms or less), and subsequently reduce exhausting retardance stimulation Frequency to about 100Hz keeping the retardance.Because relatively low frequency stimulation provides less pulse, lower frequency exhausts retardance It is more energy efficient retardance to be exhausted than upper frequency.If exhaust being arrested in about 100Hz, rather than start in 200Hz, this will need longer Time realizing exhausting retardance.According to current observation, it is believed that the retardance that exhausts under 100Hz will take for about 5 seconds to 10 Second.The use in two (or more) frequency stages can be used to obtain the benefit of each frequency, such as relatively fast using a kind of frequency Induce fastly and exhaust retardance, then relatively effectively maintain to exhaust retardance using another kind of frequency.

Various embodiments can provide selective fibre commhnication using the retardance that exhausts of SJ.Exhaust retardance Special fiber can be limited to by diameter or origin or to the position of electrode.For only some nerve fibers, will can exhaust The amplitude controlling of retardance pulse is to be only above stimulus threshold.Therefore, action potential is caused to pass although all of fiber can have Other pulses broadcast, the presynaptic ending of some fibre promptly exhausts the ability of their across synapse joint communications, because stimulating Frequency cause and exhaust retardance.Various stimulus waveforms, including non-sine or sinusoidal wave form can be used.Nonsinusoidal waveform may include directly Line pulse, may include two-phase rectangular pulse charge balance waveform, for the accurate trapezoidal and pulse triangle of unidirectional application.Make The nerve stimulation of initiation nerve traffic and desired physiological responses for a part for neural stimulation therapy can be referred to as low Frequency stimulation (for example, about 20Hz or in the range of about 0.25Hz to about 50Hz)；And exhaust frequency by contrast and can be claimed For altofrequency (for example, about 200Hz or in the range of about 100Hz to about 1kHz).Effectively activate (multiple) nerve fiber with The stimulation under these relatively low frequencies of delivering neural stimulation therapy can be referred to herein simply as " nerve stimulation " or be referred to as " the stimulation of nerve；", and the stimulation under higher " exhausting " frequency can referred to herein simply as " exhausting retardance stimulates.” " high amplitude, low frequency " (HALF) stimulus signal can exceed stimulus threshold and therefore can be used for recruit (recruit) it is little And big fiber.So, HALF signals can be used for feeling to obtain the phase with B efferent fibers by capturing all required A The effect of stimulation of prestige." little amplitude, altofrequency " (SAHF) stimulus signal can be set as such amplitude, and it exceedes less Stimulus threshold, therefore only recruit fiber that some have relatively low stimulus threshold (for example, bigger fiber or closer to (multiple) The fiber of stimulating electrode), at the same stay other fibers with higher stimulus threshold (for example, less fiber or further from The fiber of (multiple) stimulating electrode) still can be excited by HALF.Exhaust retardance and stimulate and cancel with identical or lower shake The effectiveness of all signals induced under the lower frequency (such as 20Hz) of width.SAHF can be used for realizing big fiber rather than compared with The neurotransmitter of little fiber exhausts retardance, and the big fiber is the fiber with relatively low stimulus threshold, described less Fiber is the fiber with relatively high stimulus threshold.In some embodiments, it is possible to use identical with low frequency stimulating or near Exhausting retardance like identical high amplitude delivering upper frequency stimulates, to reduce or adjust the treatment of applied use low frequency stimulating Effect.

The whether depolarization of current amplitude and pulse width control aixs cylinder, and whether the FREQUENCY CONTROL neurotransmitter for stimulating is in god Jing tips exhaust.Can be with control electric current amplitude and pulse width only selecting larger fiber for exhausting retardance.For example, can be with Control electric current amplitude and pulse width, or can with higher amplitude and/or more exhausting A fibers rather than less fiber Wide pulse width control is exhausting both A and fiber B.

By way of example, and not limitation, for the complete neurotransmitter retardance of purpose fiber can be recruited by obtaining Curve (recruitment curve) guarantees.Recruiting curve can recognize the activation threshold and saturation threshold of neural target.For It is probably specific that individual patient recruits curve, and may illustrate increases with current amplitude increase activity, then may illustrate wherein Increase the platform that the activity is not dramatically increased with current amplitude.Activation threshold reflection is to increase neural activity with current amplitude Start to increase, and saturation threshold reflection be in response to further increase neural activity in current amplitude and do not dramatically increase.Because The current amplitude that retardance stimulates can be exhausted with nargin (margin) setting higher than activation threshold, can be true based on activation threshold The fixed current amplitude for exhausting retardance stimulation.Saturation threshold represents the nerve fiber propagation action of wherein all or almost all The threshold value of current potential.Exhausting the current amplitude of retardance stimulation can be higher than and the saturation threshold based on the fiber for being expected retardance.Citing For, the amplitude for exhausting stimulus signal can be set as being close to the saturation threshold of the expected fiber for blocking, or can be set as Higher than the nargin of the saturation threshold of fiber, or the nargin of saturation threshold can also be set at less than to provide partial block.

Change due to there may be (various) patient caused by the spacing of electrode distance nerve fiber, one kind can be performed Program is determining selective fiber stimulation therapy overview (profile) of each individual patient.Due in different neural targets The different body part of nerve fiber innervation, specific procedure will depend on the specific neural target being stimulated.For example, such as Fruit targeting neck vagus nerve, then can determine the selective fiber of patient by observing laryngeal vibration and blood pressure and heart rate volatility Stimulation therapy overview.Therefore, the threshold of activation of neural target can first be found for providing the various embodiments for exhausting retardance Value and saturation threshold.Current amplitude can be chosen above the saturation threshold of neural target, and for given application can be with The frequency is selected to be sufficiently high into the ability that (such as 200Hz) is communicated with rapidly depleting presynaptic ending across synaptic space, so as to There is provided for the application and effectively exhaust retardance.The program can change the frequency of stimulation, while monitoring between different types of retardance Transition (for example, exhaust retardance and kHz conduction blocks between transition) physiological effect, or improve efficiency, or improve the time Constant (such as morbidity/restore), or to find both activate some nerve fibers and also provide for other nerve fibers and exhaust resistance Stagnant desired frequency and position.

Some embodiments can oblique ascension stimulation.Oblique ascension stimulates the retardance that can provide classification, and it can make stimulation more may be used Tolerance.For example, exhaust in retardance in neuromuscular junction, oblique ascension stimulates can be reduced by creating the initial classification retardance phase Stimulate the power of initial musculation when starting.Some embodiments can change the frequency of stimulus signal during blocking Rate.Therefore, higher frequency stimulation can be used for quickly being blocked, and then relatively low frequency stimulation can be used to keep previously obtaining The retardance for obtaining.For example, original frequency (such as 260Hz) can be used for quickly realizing exhausting retardance, be followed by second frequency (for example 130Hz) retardance is exhausted with maintenance.The frequency of stimulation is to how long completely or 90% to exhaust retardance related.For example, about 100 to about Frequency in the range of 150Hz provided 90% in about 10 seconds to 4 seconds and exhausts retardance, and in the range of about 200 to 1000Hz Frequency exhausting retardance less than providing 90% in one second (such as the ms orders of magnitude).Frequency more than 1kHz initially enters neural biography Lead retardance.

Present subject matter can be used in stimulate in vagal application or in the application for stimulating other nerves.At this Using vagus nerve as a complicated neural example discussion in text.Vagus nerve is the autonomic nervous system being discussed briefly below (ANS) a part.Fig. 6 illustrates vagal some branches of neck.Neck vagus nerve 619 is divided into the combination god of many branches Jing, including the ear branch 620 of innervation ear peripheral region, the pharynx branch 621 of the pharyngeal peripheral region of innervation, inside Recurrent laryngeal nerve 624 and the branch one of nervus glossopharyngeus of 622 laryngeal nerves, outside laryngeal nerve 623 and innervation throat peripheral region Play the heart of the sino-carotid hole nervous ramification 625 of innervation, the lung branch 626 of innervation pulmonary and innervation heart Branch 627.Vagus nerve continues the other parts of innervation body, including liver, stomach, intestinal, bladder and kidney.Innervation heart Fiber include for example less B- fibers.Have been proposed that the vagal therapy of stimulation neck, such as heart failure treatment.The possible phase Hope by this way stimulate neck vagus nerve, which activation small diameter B- fibers (parasympathetic nervouss) and do not activate compared with The A- fibers (motion) of major diameter, so that avoid may be by the activation fibrogenic undesirable side effect of A, such as but not limited to larynx Portion's vibration, cough and various offending sensations.

ANS adjusts " nonvoluntary (involuntary) " organ, and arbitrarily the contraction of (voluntary) (skeleton) muscle by Somatic movement nerve control.The example of nonvoluntary organ includes breathing and digestive organs, and also including blood vessel and heart.Generally In the case of, for example, ANS plays a role to adjust body of gland in nonvoluntary, reflexive mode, adjusts skin, eye, stomach, intestinal and bladder In muscle, and adjust myocardium and circumvascular muscle.ANS includes sympathetic nervous system and parasympathetic nervous system.Hand over Sense nervous system is relevant with the stress to emergency and " fight or flight responds (fight or flight response) ". Except other effects it is outer, " fight or flight response " increase blood pressure and heart rate to increase skeleton muscle blood flow, and reduce digestion so as to Energy is provided for " fight or flight ".Parasympathetic nervous system and lax and " rest and digestion response (rest and digest Response) " relevant, in addition to other effects, " rest and the digestion response " reduces blood pressure and heart rate, and increases digestion to protect Deposit energy.ANS maintains normal built-in function and works together with somatic nervous system.Nervus centripetalis are rushed to nerve centre transmission It is dynamic, and nervus centrifugalis transmit out impulsion from nerve centre.

Sympathetic nerve and parasympathetic nervous system is stimulated to cause heart rate, blood pressure and other physiological responses.For example, stimulate and hand over Sense nervous system expansion pupil, the nonvoluntary contraction (wriggling) for reducing saliva and mucus generation, lax muscularis of bronchus, reducing stomach Continuous fluctuation stomach function regulating motion, increase liver glycogen be converted into into glucose, reduce kidney the secretion of urine and lax wall simultaneously Closure sphincter vesicae.Stimulate parasympathetic nervous system (suppression sympathetic nervous system) to shrink pupil, increase saliva and mucus product The motion of secretions and harmonization of the stomach large intestine in raw, contraction muscularis of bronchus, increase harmonization of the stomach large intestine simultaneously increases disappearing in small intestinal Change, increase the secretion of urine and pinch wall and lax sphincter vesicae.The function related to sympathetic and parasympathetic nervous system has perhaps It is many and can intricately integrate each other.

The reduction of parasympathetic activity promotes the occurrence and development of various cardiovascular disease.Some realities of present subject matter The scheme of applying can be used to that various cardiovascular disease are treated come preventative or therapeutic by adjusting autonomous tension force.Treatment cardiovascular disease The nerve stimulation of disease can be referred to herein as neurocardiac treatment (NCT).Vagus nerve for treating cardiovascular disease is pierced Swashing can be referred to as VST or NCT.However, it is possible to VST is delivered for non-cardiovascular disease, and can be by stimulating fan absent-minded Nerve delivering NCT outside Jing.The example of cardiovascular disease or the patient's condition includes hypertension, HF and heart reconstruction.These patient's condition will It is briefly described below.

Hypertension is the reason for secondary morbidity of the heart disease heart related to other becomes.There is high blood when vasoconstriction Pressure.As a result, heart more hardy works to keep flowing under higher blood pressure, and this can cause HF.Hypertension is usually directed to High blood pressure, such as systemic arterial blood pressure are of short duration or be persistently increased to and be likely to induce Cardiovascular Damage or other adverse consequencess Level.Hypertension is defined as into systolic pressure more than 140mm Hg or diastolic pressure is higher than 90mm Hg.Uncontrolled hypertension Consequence includes but is not limited to retinal vascular disease and apoplexy, left ventricular hypertrophy and exhaustion, myocardial infarction, dissecting aneurysm and kidney Angiopathy.Most population, and most implants cardiac pacemaker or the patient of defibrillator suffers from high blood Pressure.For this colony, if can reduce blood pressure and hypertension, long-term mortality and quality of life can be changed It is kind.Many patient for treatment with hypertension are without response, such as related to lifestyle change and hypertension drug treatment.

HF refers to a kind of clinical syndrome, and wherein cardiac function causes subnormal cardiac output, and it can be less than and be enough to Meet the level of the metabolic demand of peripheral tissues.Due to adjoint vein and pulmonary congestion, HF itself can be rendered as the congested heart Dirty exhaustion (CHF).HF can be due to Different types of etiopathogenises, such as ischemic heart disease.HF patient has impaired autonomic balance, this It is relevant with LV functional defecies and mortality rate increase.

Heart reconstruction refers to the complicated remodeling process of ventricle, and it is related to structure, biochemistry, neuro hormone and electro physiology factor, its Subsequent myocardial infarction (MI) can be caused or kinemic other causes of disease are reduced.Ventricular Remodeling is touched by physiological compensation mechanism Send out, the mechanism increases cardiac output due to so-called backward sexual exhaustion, this increases the diastole filling pressure of ventricle and thus increases Plus so-called prestrain (preload) (that is, the journey that ventricle is stretched by the volume of the blood in ventricle at the end of diastole Degree).The increase of prestrain causes the increase of stroke volume, one kind to be referred to as Frank-Starling principles between systolic period Phenomenon.But, when ventricle is stretched because of the prestrain of the increase of a period of time, ventricle becomes expansion.Ventricular volume Expansion causes the ventricle wall stress of the increase under given systolic pressure.Together with the pressure-volume work of the increase done by ventricle, This serves as the stimulation of ventricle muscular hypertrophy.The disadvantage of expansion is the extra work load forced in normal residual myocardium With the increase (Laplace laws) of wall tension force, it represents the stimulation of hypertrophy.If hypertrophy is not enough to match increased tension force, Vicious cycle then occurs, and this causes further and progressive expansion.When heart starts expansion, incoming pressure receptor The vasculomotor central nervous system control centre of impact is sent to cardiopulmonary receptor signal, it is with hormone secretion and sympathetic god Jing electric discharges are used as response.Hematodinamicss, sympathetic nervous system and hormone change (such as turn presence or absence of angiotensin Change enzyme (ACE) activity) combination cause participation Ventricular Remodeling cellularity in harmful change.Cause the sustained stress of hypertrophy The apoptosis (that is, programmed cell death) of inducing cardiomyocytes and final wall are thinning, and this causes cardiac function further to deteriorate. Therefore, although ventricular dilatation and hypertrophy can first be compensated and be increased cardiac output, however the process ultimately result in contraction and Diastolic dysfunction.Have shown that after the degree and MI of Ventricular Remodeling and the mortality rate of heart failure patients increases positive correlation.

Vagus nerve has many nervous pathways recruited with different stimulus thresholds.Various lifes to vagal stimulation Reason response is relevant with the various threshold values of VST intensity.The intensity of (multiple) parameter regulation VST of regulation stimulus signal can be passed through. For example, the amplitude of signal (for example, curtage) can be increased to increase the intensity of signal.(multiple) other thorns can be adjusted Replacement or supplement of the sharp parameter as amplitude.For example, stimulus intensity can be with the frequency of stimulus signal, boost pulse string frequency (burst frequency), pulse width and/or dutycycle and change.

For example, Fig. 7 illustrates the VST intensity increased to the right from the left side of figure, and also illustrates that the various physiology caused to VST The intensity threshold of response.VST causes strength ratio VST residing for physiological responses " A " to cause the low intensity residing for physiological responses " B ", VST causes strength ratio VST residing for physiological responses " B " to cause the low intensity residing for physiological responses " C ".In other words, VST is reaching Cause response " A " to after the intensity (such as stimulus threshold) of certain level, reach higher intensity (for example, higher stimulation Threshold value) cause response " B " afterwards together with response " A ", and reaching intensity (for example, the threshold of stimulation of even more high of even more high Value) cause response " C " afterwards together with response " A " and " B ".

As has been recognized, VST can be used to treat cardiovascular disease.VST to cardiac function and the beneficial effect reinvented not It is certain to reduce mediating by heart rate.That is, VST can be beneficial to patient and make not with the undesirable chronotropic associated with VST With and other side effect for causing are stimulated by high intensity, such as cough, muscular irritation.And, than realizing that heart rate reduces institute Cause antiinflammatory, anti-sympathetic nerve and anti-apoptotic medium under the VST intensity of the low intensity at place.These media serve as a kind of approach, lead to Cross approach VST and provide therapeutic effect for cardiovascular disease.Physiological responses under relatively low VST intensity to cardiovascular disease such as HF has therapeutically effective result.These responses are for these treatment mediations or provide approach.It is beneficial to HF under relatively low VST intensity This response example include antiinflammatory, anti-sympathetic nerve and anti-apoptotic response and nitric oxide (NO) increase.May not the phase Hope the physiological responses under higher VST intensity.Response to the higher VST intensity of the ability of patient tolerance VST can be reduced Example includes, but not limited to reduce heart rate, extends AV conduction, vasodilation and cough.Furthermore, it is possible to not expect relatively low yet VST intensity under some physiological responses.For example, patient may be found that larynx vibration is offending.In these responses at least Some are desired possibly for some therapies, but for other therapies are undesirable.By way of example, and not limitation, It may be desirable to reduce heart rate and/or extend the VST of AV conduction to treat some cardiovascular disease, but for other are probably not phase Hope.The intensity of (multiple) parameter regulation VST of regulation stimulus signal can be passed through.For example, signal (for example, electricity can be increased Stream or voltage) amplitude increasing the intensity of signal.(multiple) other stimulus parameters can be adjusted as the replacement or benefit of amplitude Fill.For example, stimulus intensity can be with frequency (for example, the frequency of boost pulse), the boost pulse string frequency (example of stimulus signal Such as, the multiple trains of pulse for transmitting for the burst frequencies of start bursts, wherein each train of pulse include multiple pulses), Pulse width and/or dutycycle and change.

Present subject matter can be used for the intensity of setting or threshold limit, with the undesirable shadow for avoiding high intensity from stimulating Ring, and can be used for affecting to provide to exhaust retardance for some under relatively low stimulus intensity are undesirable.For example, can hold Row exhausts and blocks to block response " A " and can set the intensity of stimulation to avoid responding " C ", so as to leave the phase to stimulating Hope response " B ".Provided herein is some embodiments can provide presynaptic ending block to be arrested in lower threshold under the non-phase Activation is hoped, can such as cause laryngeal vibration, while VST intensity of the transmission higher than lower limit.By blocking the not phase at lower thresholds The activation of prestige, it may increase the intensity for stimulating with fibers needed for capturing more and improve the Expected Response to stimulating.

Fig. 8 illustrates the VST intensity increased to right side from the left side of figure, and further illustrates the undesirable life caused to VST The intensity threshold of reason response, it is used to limiting the upper limit of VST intensity, and causes another physiological responses to VST another Intensity threshold.For example, for the VST intensity thresholds of cough can serve as the upper limit, and for the VST intensity of laryngeal vibration response Threshold value can serve as lower limit.In some embodiments, the physiological responses for limiting the upper limit are the muscular irritations for detecting.Big muscle Stimulate or external irritant is probably to make patient worried.A fibers and then the increase for causing laryngeal vibration can be passed through to recruit first Intensity sets vagus nerve capture threshold value until detecting cough side effect.Intensity settings are being caused into the intensity of laryngeal vibration And cause between the intensity of cough.For example, if increasing the amplitude of stimulus signal to increase VST intensity and if 1.0mA draws Play laryngeal vibration and 2.5mA causes cough, then pace-making amplitude can be set as 1.0 to 2.4mA.Can be applied with appropriate stimulus parameter Plus exhaust and block to block other undesirable responses that VST causes laryngeal vibration or causes under relatively low amplitude.

Fig. 9 A-9C go forward side by side one using the schematic representations of the different stimulated threshold value of the different fiber types in complicated nerve 928 Walk and exhaust the various combination explanation selective stimulating that retardance stimulates using nerve stimulation and presynaptic ending.By example rather than limit The mode of system, each figure of Fig. 9 A-9C includes being configured to deliver nerve stimulation and presynaptic ending exhausts the bipolar of retardance stimulation Stimulate lead 929.The design for illustrating in these figures goes for other kinds of stimulation, and such as unipolar stimulation and multipole are pierced Swash.Accompanying drawing provides the schematic representations of nerve, and by simple example three kinds of stimulus thresholds are shown, Jing is defined as less threshold Value, intermediate. threshold and larger threshold value.The threshold value of given fiber depend on its fiber type and its relative to stimulating electrode Position.However, the design can be simplyd illustrate based on fiber size.Schematic representations in Fig. 9 A-9C show with compared with The A fiber types of the large-size of little stimulus threshold, the middle-sized Type B fiber with medium stimulus threshold, and have The c-type fiber of the reduced size of larger stimulus threshold.Fig. 9 A show that the middle-sized Type B with medium stimulus threshold is fine The selective stimulating of dimension.Nerve stimulation has the parameter more than A and the stimulus threshold of fiber B, and exhausts retardance with more than A The parameter of the stimulus threshold of fiber.Therefore, nerve stimulation and exhaust the combination of retardance and cause only effectively to stimulate fiber B, because Only fiber B can be communicated across the synaptic space of each of which.Fig. 9 B show the medium chi with medium stimulus threshold Very little Type B fiber and the selective stimulating of the fiber C of the reduced size with small threshold.Nerve stimulation has more than A, B and C The parameter of the stimulus threshold of fiber, and exhaust the parameter that retardance has the stimulus threshold more than A fibers.Therefore, nerve stimulation Cause only effectively to stimulate B and fiber C with the combination for exhausting retardance, because only that B and fiber C can be across the synapses of each of which Gap is communicated.Fig. 9 C show the selective stimulating of the fiber C of the reduced size with small threshold.Nerve stimulation has More than the parameter of the stimulus threshold of A, B and fiber C, and retardance is exhausted with the parameter more than A and the stimulus threshold of fiber B. Therefore, nerve stimulation and exhaust the combination of retardance and cause only effectively to stimulate fiber C, because only that fiber C can be each across them From synaptic space communicated.

Figure 10 illustrates first group of aixs cylinder 1030 in the nerve captured by nerve stimulation and stimulates capture by retardance is exhausted Second group of aixs cylinder 1031, wherein, second group of aixs cylinder is the subset of first group of aixs cylinder.Nerve stimulation is more than for first group of stimulation The threshold value of aixs cylinder, therefore action potential will be caused to propagate in first group of larger aixs cylinder.However, exhausting retardance will prevent aixs cylinder The presynaptic ending of subset conduct across the synaptic space of each of which, and only the remainder of first group of aixs cylinder is effectively Across synaptic space communication.

Figure 11 A-11M are illustrated and are used for exhausting the one of the electrode configuration that retardance stimulates delivery of selective nerve stimulation A little examples.These examples are not intended to show all possible electrode configuration.Electrode configuration can be that bipole arrangement or one pole are matched somebody with somebody Put.Additionally, the interval between electrode can be different from shown.In addition, these examples are not intended to necessarily represent nerve stimulation And exhaust retardance stimulate between timing.Some embodiments can interrupt to exhaust to block stimulates (such as 200Hz) to provide the time Window, delivers the pulse of nerve stimulation (for example, 20Hz) in the time window, so as to avoid using multiple negative electrodes and/or multiple sun Pole delivers two signals simultaneously.Can be with the polarity of switching signal.Some embodiments can share a negative electrode for nerve pierce Swashing and exhaust retardance stimulates, and some embodiments can share an anode to be used to nerve stimulation and exhaust to block stimulate.

Figure 11 A illustrate that wherein first electrode 1132 and second electrode 1133 are used to deliver nerve stimulation 1130 and also be used for Delivering exhausts the electrode configuration of retardance 1131.There may be some anatomical locations and be more suitable for using some it compared to other The stimulation of his electrode arrangement.Some in these are illustrated below.Some embodiments can be configured to be can use on lead Electrode between electronics switching stimulus vector.Figure 11 B show a kind of electrode configuration, and it includes that first electrode 1132, second is electric The electrode 1134 of pole 1133 and the 3rd, the wherein electrode 1134 of first electrode 1132 and the 3rd exhaust retardance 1131 and first for delivering The electrode 1134 of electrode 1132 and the 3rd is used to deliver nerve stimulation 1130.Figure 11 C show a kind of electrode configuration, and it includes first Electrode 1132, the electrode 1134 of second electrode 1133 and the 3rd, the wherein electrode 1134 of first electrode 1132 and the 3rd is used to deliver god Jing stimulates 1130, and the electrode 1134 of second electrode 1132 and the 3rd is also used for delivering and exhausts retardance 1131.Figure 11 D show one Kind of electrode configuration, it includes first electrode 1132, the electrode 1134 of second electrode 1133 and the 3rd, wherein first electrode 1132 and the Two electrodes 1133 exhaust retardance 1131 for delivering, and the electrode 1134 of second electrode 1133 and the 3rd is used to deliver nerve stimulation 1130.Figure 11 E show a kind of electrode configuration, and it includes first electrode 1132, the electrode 1134 of second electrode 1133 and the 3rd, its The electrode 1134 of middle second electrode 1133 and the 3rd is used to deliver nerve stimulation 1130, and the electrode of first electrode 1132 and the 3rd 1134 exhaust retardance 1131 for delivering.Figure 11 F show a kind of electrode configuration, and it includes first electrode 1132, second electrode 1133 and the 3rd electrode 1134, the wherein electrode 1134 of first electrode 1132 and the 3rd exhausts retardance 1131, Yi Ji for offer Two electrodes 1133 and the 3rd electrode 1134 are used to provide nerve stimulation 1130.Figure 11 G show a kind of electrode configuration, and it includes One electrode 1132, the electrode 1134 of second electrode 1133 and the 3rd, wherein first electrode 1132 and second electrode 1133 are used to deliver Nerve stimulation 1130, and the electrode 1134 of first electrode 1132 and the 3rd exhausts retardance 1131 for delivering.Figure 11 H show one Electrode configuration is planted, it includes first electrode 1132, second electrode 1133, the 3rd electrode 1134 and the 4th electrode 1135, wherein the One electrode 1132 and second electrode 1133 exhaust retardance 1131 for delivering, and the 3rd electrode 1134 and the 4th electrode 1135 are used In delivering nerve stimulation 1130.Figure 11 I show a kind of electrode configuration, it include first electrode 1132, second electrode 1133, Three electrodes 1134 and the 4th electrode 1135, wherein first electrode 1132 and second electrode 1133 are used to deliver nerve stimulation 1130, And the 3rd electrode 1134 and the 4th electrode 1135 exhaust retardance 1131 for delivering.Figure 11 J show a kind of electrode configuration, its Including first electrode 1132, second electrode 1133, the 3rd electrode 1134 and the 4th electrode 1135, wherein first electrode 1132 and Four electrodes 1135 are used to deliver nerve stimulation 1130, and the electrode 1134 of second electrode 1133 and the 3rd exhausts retardance for delivering 1131.Figure 11 K show a kind of electrode configuration, and it includes first electrode 1132, second electrode 1133, the 3rd electrode 1134 and Four electrodes 1135, the wherein electrode 1135 of first electrode 1132 and the 4th exhausts retardance 1131, and second electrode for delivering 1133 and the 3rd electrode 1134 be used to deliver nerve stimulation 1130.Figure 11 L show a kind of electrode configuration, and it includes first electrode 1132nd, second electrode 1133, the 3rd electrode 1134 and the 4th electrode 1135, the wherein electrode 1134 of first electrode 1132 and the 3rd is used Retardance 1131 is exhausted in delivering, and the electrode 1135 of second electrode 1133 and the 4th is used to deliver nerve stimulation 1130.Figure 11 M show Go out a kind of electrode configuration, it includes first electrode 1132, second electrode 1133, the 3rd electrode 1134 and the 4th electrode 1135, The wherein electrode 1134 of first electrode 1132 and the 3rd is used to deliver nerve stimulation 1130, and the electrode of second electrode 1133 and the 4th 1135 are used for delivering exhausts retardance 1131.

Figure 12 illustrates by way of example, and not limitation nerve stimulation and exhausts the concurrently delivering that retardance stimulates.For example, Various embodiments can provide a kind of stimulator, and it can deliver retardance waveform is used to block A fibers, while delivering treatment ripple Shape is used for the EAP in fiber B.In one more specifically example, it is possible to use the frequency of 200Hz is being enough to reach Stimulus threshold but e insufficient to A fibers reaches the low current amplitude retardance A fibers of the stimulus threshold of fiber B.Such thorn Energizing signal can effectively block A fibers but not block fiber B.Drive fiber B in action potential therapy can under 20Hz and Sufficiently achieve and delivered under the high current amplitude of A fibers and the stimulus threshold both fiber B.Because A fibers are by under 200Hz frequencies Retardance is exhausted with the presynaptic ending under low current amplitude to be blocked, action potential will not be driven by 20Hz signals.Combination Waveform can be on a bipolar electrode.Compared to each other, 20Hz signals have relatively high amplitude and relatively low frequency, because This can be referred to as high amplitude low frequency (HALF) signal；And 200Hz signals have relatively small amplitude and relatively high frequency, and And therefore little amplitude and high frequency (SAHF) signal can be referred to as.The activation of therapeutic B- fiber causes the reduction of HR, and locks not The A- fibers of needs stop laryngeal vibration.

Figure 13 illustrates by way of example, and not limitation concurrent nerve stimulation and exhausts the intermittent delivery that retardance stimulates.Between The stimulation ON times that delivering of having a rest includes being separated by stimulation OFF time.ON time schedulings can will be stimulated to be occur in programming time, For example program time started and programming dwell time, or programming time started and programming persistent period.The example bag of intermittent delivery Include 10 seconds ON/50 second OFF.For example, the ON periods are stimulated to be probably the time period between 1/4 second and 150 seconds, And stimulate OFF period to be the time period between 1 second and 150 seconds.The startup for exhausting retardance is sufficiently fast, so as to short time outburst. The ON times are stimulated to be triggered by the event for detecting.The event for detecting is probably to receive patient's order or clinician's order. The event for detecting can be the event for detecting from sensing (multiple) parameter determination.For example, such as by Figure 13 in it is intracardiac Shown in one example of signal, when using the parameter for sensing, the such as spy of heart rate or ECG, heart sound or blood pressure detecting cardiac cycle When determining part, stimulation can be triggered.The persistent period of the stimulation delivered in response to the event for detecting can be consolidating for programming Determine event or changed according to the frequency of the event for being detected or the event for detecting.For example, the time window for stimulating for delivering can To shorten in response to the increase of the speed for stimulating.

Figure 14 illustrates by way of example, and not limitation an example of selectivity nerve fiber stimulation system.The system 1436 may be coupled to stimulating electrode 1437.System 1436 can include stimulator 1438 and be operably connected to stimulator 1438 with the controller 1439 of the delivered stimulation of control.Controller 1439 can include exhausting retardance controller 1440 and nerve Boost controller 1441, and stimulator 1438 can include exhausting retardance stimulator 1442 and nerve stimulator 1443.Exhaust Retardance controller 1440 can be operably connected to and exhaust retardance stimulator 1442 to control to have in about 100Hz to about 1kHz In the range of frequency exhaust retardance stimulate delivering.For some selectivity nerve fiber stimulation embodiments, will can be somebody's turn to do Exhausting retardance stimulates referred to as SAHF.Neurostimulation controller 1441 can be operably connected to nerve stimulator 1443 to control The delivering of the nerve stimulation with the frequency in the range of about 0.25Hz to about 50Hz.For example, the frequency of nerve stimulation signal can Being of about 20Hz.This nerve stimulation signal can be referred to as HALF signals.

Figure 15 illustrates by way of example, and not limitation an example of selectivity nerve fiber stimulation system.System 1536 is similar to Figure 14, including controller 1539, and it includes exhausting retardance controller 1540 and neurostimulation controller 1541, also Including stimulator 1538, it includes exhausting retardance stimulator 1542 and nerve stimulator 1543, these with Figure 14 in show and retouch Those stated are similar.Controller 1539 can also include the time block 1544 of the timing for being configured to control to stimulate.Can be with each Plant different modes and control timing.Time block can be configured to control to exhaust the timing blocked with both nerve stimulations.Example Such as, time block can control the start and stop time for exhausting both retardance and nerve stimulation.Time block is controllable to exhaust resistance The beginning of both stagnant and nerve stimulations and persistent period.Time block can exhaust retardance with control break stimulates or changes nerve thorn Sharp timing.For example, time block is controllable exhausts retardance stimulus frequency to the second change for exhausting retardance stimulus frequency from first Change.Time block can control the relative timing exhausted between retardance and nerve stimulation.For example, exhausting retardance stimulation can depend on The timing of nerve stimulation.In addition, exhaust retardance stimulation can be interrupted, to provide the window of the pulse for wherein delivering nerve stimulation Mouthful.Exhausting retardance can simultaneously start with nerve stimulation, or can the startup of nerve stimulation somewhat before or after open It is dynamic.For example, according to table 2,200Hz signals exhaust retardance signal can be before nerve stimulation started less than one second so that in god Jing stimulates the retardance for starting to realize more than 90% before.As being generally illustrated 1545, regularly can be based on clinician or trouble The order of person or other inputs, or biosensor can be based on, for example, by way of example, and not limitation, breathing is passed Sensor, blood pressure sensor, blood flow transducer or the cardiac sensor that can include with regard to cardiac cycle and heart rate information.

Controller 1539 can also include titration control module 1546.The titration control module can be used for regulation and exhaust resistance Stagnant stimulation, to control by the aixs cylinder for exhausting retardance stimulation capture, for adjusting nerve stimulation to control what is captured by nerve stimulation Aixs cylinder, or stimulate and nerve stimulation while adjusting and exhausting retardance.The amplitude of stimulation, or scalable pulse width can be adjusted, or Both scalable amplitude and pulse width, to control captured aixs cylinder.

Titration as used herein refers to the process of that adjusting the dosage most Zhongdao for stimulating treats or prevent effectively level, institute It can exhaust retardance to stimulate to state stimulation, nerve stimulation or exhaust retardance and both nerve stimulations.Effectively exhausting retardance stimulates Can be have effectively capture desired aixs cylinder amplitude and pulse width, blocker frequency is exhausted, (such as 100Hz is extremely Stimulation under 1kHz).Effectively nerve stimulation can have the amplitude and pulse width that effectively capture desired aixs cylinder , stimulation under nerve stimulation frequency (for example, 0.25Hz to 50Hz, such as about 20Hz).Additionally, nerve stimulation also has " dosage " component, to provide the stimulation of effective dose, so as to provide required treatment.Dosage is included in the nerve in frame preset time The amount or intensity of stimulation, and it is additionally included in the number of times of delivering nerve stimulation in a period of time.Can be such as refreshing by regulation parameter Amplitude, dutycycle, persistent period and/or the frequency or the quantity of the nerve stimulation event occurred within a period of time that Jing stimulates is adjusted The intensity of section nerve stimulation.Titration procedure can occur during implant procedure, or during follow-up clinical interview, or when patient from When enabling is examined clinical setting and is not liied in bed.Based on device programming, titration doctor's control or can be automatically controlled.Such as 1545 substantially Illustrate, titration can be based on the order or other inputs of clinician or patient, or can be based on biosensor, example Such as, by way of example, and not limitation, respiration pickup, such as ventilation quantity sensor per minute, blood pressure sensor, blood flow is passed Sensor, impedance transducer, accelerometer, electromyogram (EMG) sensor or the letter that can include with regard to cardiac cycle and heart rate information The cardiac sensor of breath, for example, be configured to detect the sensor of electrocardiogram (EKG).Cardiac sensor can include for example electrode and Heart sound transducer.

As shown in figure 13, nerve stimulation and/or to exhaust retardance can be intermittent.By way of example, Figure 16 shows Go out the expression of intermittent nerve stimulation (INS).Accompanying drawing is shown schematically in the stimulus intervalses for ON and the stimulus intervalses for OFF Between alternate nerve stimulation time course, when boost pulse (that is, the train of pulse for delivering a boost pulse or set of group 1647) when, stimulus intervalses are ON, and when boost pulse is not delivered, stimulus intervalses are OFF.Thus, for example, some embodiments Multiple single-phase or diphasic pulse in the neural stimulation pulses string illustrated in Figure 16 is provided.The pulse of delivering can in train of pulse 1647 To be delivered with pulse frequency.These pulses also have amplitude.Both pulse frequency and pulse amplitude affect neural stimulation therapy Dosage.The persistent period for stimulating ON intervals is sometimes referred to as stimulus duration or burst duration.Train of pulse continues Time also affects the dosage of neural stimulation therapy.Stimulate ON intervals is initially temporary transient reference point NS event.Continuous NS events Between time interval be INS interval, it is sometimes referred to as stimulation period or burst periods 1648.Burst periods 1648 are sent out The quantity of the raw nerve stimulation event within a period of time also affects the dosage of nerve stimulation.When the application of nerve stimulation is interval Property when, stimulus duration (that is, ON intervals) less than apply nerve stimulation when stimulation period (that is, INS intervals).Between the OFF of INS Every persistent period by ON interval and INS interval persistent period determine.ON is spaced the persistent period (example relative to INS intervals Such as, it is expressed as ratio) it is sometimes referred to as the dutycycle of INS.

Doctor or clinician can control the regulation of one or more neural stimulation parameters, to control stimulus intensity.For example, Wherein stimulating electrode be implanted in vagus nerve or other nerve stimulation targets near implant procedure during, doctor or clinic Doctor can adjust (multiple) stimulus parameter to adjust stimulus intensity, stimulate so as to be properly located electrode and programming, to provide The threshold value of neural target stimulates, and it provides desired physiological effect.In view of the migration of electrode, the resistance in electrode/organizational interface Anti- change etc., doctor or clinician can during subsequent access the implantable nerve stimulator of reprogramming.It is follow-up to visit In asking, doctor or clinician can control the regulation of one or more neural stimulation parameters, to control stimulus intensity, so that it is determined that The neural stimulation intensity of the physiological responses needed for providing.Titration procedure can be the implantable nerve being implanted in Non-staying in bed patient The automated procedure of stimulation apparatus.Automatic Titration program can manually be touched by the signal from patient or by doctor or clinician Send out.Automatic Titration program can pass through the timetable of programming or be triggered automatically by the event for sensing.

Figure 17 is illustrated in the controller 1439 that may be incorporated in Figure 14 or Figure 15 according to various embodiments 1539 Memorizer 1749.Memorizer 1749 can include instruction 1780, can be operated by boost control circuit, for by defined parameters collection Rise (up-titration) titration procedure that progressively tightens control of (for example, 1～parameter set of parameter set N), each of which collection The stimulating dose or intensity of stimulation therapy is altered in steps (increase or decrease).Memorizer can include multiple neural stimulation parameters Collection, wherein each collection include the unique combination of the parameter value for nerve stimulation, and wherein each unique combination of parameter value It is defined as providing neural stimulation therapy under an intensity level.The instruction comprises instructions that it is used for according to timetable The intensity of change (increasing or decreasing) treatment is stepped to by multiple neural stimulation parameter collection, until the treatment is in desired Long-term strength.Various embodiments provide such nerve stimulation program, and it finds to provide desired treatment intensity level automatically Desired treatment parameter (such as amplitude, pulse width, dutycycle) combination.

Figure 18 illustrates the one of the treatment titration module 1851 for the part that can be titration control module 1546 in Figure 15 Individual embodiment.According to various embodiments, the controller is suitable to set or adjust any one of stimulation characteristic 1852 or appoints Meaning combination.The example of stimulation characteristic includes amplitude, frequency, polarity and the wave morphology of stimulus signal.Some of stimulation output circuit Embodiment is suitable to produce the stimulus signal with predetermined amplitude, form, pulse width and polarity, and is further adapted for control Signal respond to change amplitude, wave morphology, pulse width and polarity at least one.Some realities of neural stimulation circuit The scheme of applying is suitable to produce the stimulus signal with preset frequency, and is further adapted for making sound to the control signal from controller Should be with the frequency of modification stimulus signal.

Treatment titration module 1851 can be programmed to change electrode group or electrode configuration or change stimulation location 11853, Such as change for neural target stimulating electrode or change neural target for nerve stimulation.For example, different electrodes can use Can be used to stimulate different neural targets in neural target, and different electrodes is stimulated.Can be using different electrode group/match somebody with somebody Put stimulation neural target to determine the desired low stimulus threshold for the neural target.Different neural targets can be included not Same nervous pathway, such as right and left vagus nerve and their branch, pressure receptor region, chemoreceptor region, neck are moved Arteries and veins hole and carotid sinus nerve.Different neural targets potentially includes (for example, absent-minded along neck fan along the diverse location of nervous pathway More afterbody targets or more cranium targets of Jing).Autonomic nerve target can include afferent pathway and efferent pathway, and Sympathetic nerve and parasympathetic nervouss can be included.The stimulation can include stimulating the stimulation of nerve traffic (neural traffic) Or the stimulation of suppression nerve traffic.Therefore, causing the stimulation of sympathetic response can be related to sympathetic stimulation and/or secondary friendship Sense nerve suppresses；And cause the stimulation that parasympathetic nervouss are responded to be related to parasympathetic stimulation and/or sympathetic nerve suppression System.

Treatment titration module 1851 can be programmed to change stimulus vector (vector) 1854.Vector may include between electrode Stimulus vector or the stimulus vector for changer.For example, the stimulus vector between two electrodes can be overturned.Electrode is more Complicated combination can be used to provide the more potential stimuluss vector between electrode.

Treatment titration module 1851 can be programmed to according to storage stimulation instructions such as stimulation programs in memory or Timetable 1855 controls nerve stimulation.Nerve stimulation can be delivered with boost pulse string, and it is a succession of thorn at a predetermined frequency Sharp train of pulse.Boost pulse string can be characterized by burst duration and impulse-train pause.Train of pulse it is lasting when Between be the lasting duration of train of pulse.Impulse-train pause can be determined by the time between the beginning of continuous train of pulse.Pulse The programming mode of string can include the combination in any of burst duration and impulse-train pause.When continuing with a train of pulse Between and the simple pulse string mode of impulse-train pause can periodically continue a programming cycle or can be according to more complicated Timetable.The programming mode of train of pulse can be made up of with more complicated multiple burst durations and impulse-train pause sequence.Arteries and veins Punching string programming mode can be characterized by dutycycle, the dutycycle refer to one section of set time nerve stimulation ON and The repetition period of the nerve stimulation OFF of one section of set time.Dutycycle is specified by ON times and cycle time, and therefore can be with With ON times/cycle time unit.According to each pulse control that some embodiments, control circuit pass through startup stimulus signal Make the nerve stimulation produced by stimulation circuit.In some embodiments, boost control circuit starts stimulus signal train of pulse, its Moderate stimulation signal is responded from controller circuitry by producing the train of pulse with predetermined frequency and burst duration Order.The preset frequency and burst duration of train of pulse can be programmable.The pattern of the pulse in train of pulse can be with Be have a burst duration and impulse-train pause simple pulse string mode or can be according to multiple trains of pulse Persistent period and the more complicated pulse string mode of impulse-train pause.In some embodiments, boost control circuit control thorn Sharp output circuit is starting nerve stimulation session (session) and terminate nerve stimulation session.Under the control of control circuit The burst duration of nerve stimulation session can be programmable.Controller can also terminate nerve in response to interrupt signal Stimulate session, parameter that interrupt signal such as can be sensed by one or more or wherein determine and expect to stop nerve stimulation Any other condition produce.A kind of equipment may include to store programmed treatment time table in memory or program, and And can also include can be used to perform the clock or timer of programmable stimulation time table.For example, doctor can be based in one day Time programming treatment daily/timetable weekly.Session is stimulated to start in the first programming time, and can be in the second programming Time terminates.Various embodiments are based on the signal enabling triggered by user and/or terminate stimulating session.Various embodiments make Stimulation session is enabled and/or disabled with the data of sensing.According to various embodiments, stimulation time table refers to delivering nerve thorn Swash time interval or the time period for the treatment of.Timetable can be limited by time started and end time, or by the time started and Persistent period limits.Various timetables periodically deliver treatment.By way of example, and not limitation, available treatment timetable Programming device, with the delivering treatment from midnight to 2AM daily, or delivering treatment one hour per six hours, or delivering treatment daily Two hours, or according to more complicated timetable delivering treatment.Various equipment embodiments are according to depending on the condition for allowing Programming time top application adds treatment, during the motion that the condition of the permission is such as sensed, patient's rest or sleep, specific position Put/posture, low heart rate level etc..For example, stimulation can be synchronized to cardiac cycle by the event for being stimulated based on the realization for detecting. Treatment time table can also specify how that delivering stimulates.

Figure 19 illustrates an embodiment for searching the program of threshold value for each electrode configuration.The program for illustrating is one Increase the intensity of neural stimulation therapy in the section time.Intensity is increased with increment 1956, it is not necessarily equal increment.Shown Embodiment in, perform threshold determination sequence 1957 to detect lower limit physiological responses to nerve stimulation, such as laryngeal vibration is rung Should.In titration process, laryngeal vibration is possibly desired, because it confirms vagal capture, and the value can be with For determining appropriate stimulation for the nerve stimulation on lower limit.In various embodiments, side effect detection program is performed 1958 upper limit physiological responses (for example coughing) with detection to nerve stimulation.Thus, for example, some embodiments can set down Neural stimulation intensity between limit (such as laryngeal vibration) and the upper limit (such as cough), and can set and exhaust retardance and stimulate by force Degree lower limit (such as laryngeal vibration) or lower limit somewhat on, but under the intensity of neural stimulation intensity.Such threshold value Program avoids the side effect (for example coughing) on the upper limit, if also avoiding not exhausting what retardance will occur under lower limit Side effect (such as laryngeal vibration).Some embodiments reduce the intensity of NCT treatments within a period of time, to detect to nerve thorn Sharp expectation or undesirable physiological responses.

Some embodiments use sensors to Monitoring lower-cut (such as laryngeal vibration) and the upper limit (such as cough or phrenic nervess Capture).At least some sensor can be a part for implantable devices, and the implantable devices are as being used to stimulate target nerve Implantable nerve stimulator.In some embodiments, at least some sensor is programmable device/PSA (pacing system analyzer) A part.The example of sensor includes pressure transducer, accelerometer, ventilation quantity sensor per minute, impedance transducer, configuration Into detection electrocardiogram (EKG) sensor, be configured to detect electromyogram (EMG) sensor and blood pressure sensor.Some enforcements Scheme uses the feedback from patient or doctor.For example, the click pad (clicker pad) with pain Assessment or other scales Can be used for allowing whether patient's offer carries with regard to stimulating whether to provide laryngeal vibration or other desired responses and stimulate The feedback of other the undesirable physiological responses for cough or phrenic nervess capture or to stimulating.The algorithm can in programmable device, or In implantable devices, or in the external equipment for being configured to be communicated with programmable device and/or implantable devices for example in patient Perform in management system.

Some system implementation plans are designed to sense laryngeal vibration to confirm vagal capture, then with Jing choosings Select intensity (for example, the amplitude) delivering to capture the aixs cylinder with relatively low stimulus threshold and exhaust retardance to vagus nerve to block Laryngeal vibration, and stimulated to capture the intensity (example of the aixs cylinder with higher stimulus threshold higher than exhausting to block with chosen Such as, amplitude) delivering nerve stimulation, and the treatment for delivering provides desired physiological responses.Can hold during implant procedure The confirmation of row capture.Some implantable systems, such as be implanted in Non-staying in bed patient for heart failure, hypertension or other are slow The system that sexually transmitted disease (STD) condition provides long-term treatment, can be configured to interruption and exhaust retardance, to confirm that the implantable system is capturing fan Walk nerve.Confirmation process can be started in response to the order of clinician or patient or according to timetable.

The confirmation of capture is may be implemented in a variety of ways, including using external sensor, patient's input or the sight of clinician Examine report.For example, clinician can be placed on finger in throat to feel laryngeal vibration.Can be used for the system for confirming capture An example figure 20 illustrates, it generally illustrates right vagus nerve 2059 and is branched off with nerve from right vagus nerve Prop up the recurrent laryngeal nerve 2060 of the laryngeal muscles 2061 near gas-distribution pipe 2062.Also there is left vagus nerve (not shown) and be confused absent-minded from left Jing is branched off with the recurrent laryngeal nerve (not shown) of the laryngeal muscles near innervation trachea.Laryngeal muscles activity checking is sensed by EMG The ability of vagal capture can be used together with the stimulation of right and/or left vagus nerve.Recurrent laryngeal nerve is in laryngeal muscles tail position Place is branched off from vagus nerve, then loops back to cranium (cranially) with innervation laryngeal muscles.This ring is relatively tediously long Nervous pathway, it provides between the time of vagal stimulation pulse and the time of laryngeal muscles activation and postpones.Due to the delay, After the pulse larynx activation can be determined by EMG sensors and be passivated without stimulus artifact.Additionally, the ring is absent-minded to adjust fan The distance between Jing stimulation location and laryngeal muscles provide selection.For example, in the embodiment shown in Figure 20, stimulating electrode can be put Put at the stimulation location 2063 of relatively close point 2064 to stimulate vagus nerve, recurrent laryngeal nerve is from vagus nerve at point 2064 It is branched off, and (multiple) EMG sensors can be placed along vagus nerve at the EMG of close laryngeal muscles sensings position 2065 To improve the detection of laryngeal muscles activity and reduce potentially from the interference of boost pulse.Stimulating electrode and (multiple) EMG sensors Can be on same lead.10 μm of A fibers for assuming the muscle of innervation throat have the conduction velocity of 0.17ms/cm, and And it is 50-60cm to assume from vagal stimulation sites into recurrent laryngeal nerve and return to the travel distance of laryngeal muscles, then larynx The muscle in portion activates the about 8.33-10ms after vagus nerve is upset.Therefore, because relatively long travel distance, larynx Response of the flesh to vagal stimulation has relatively long time delay.Actual range from stimulation location to laryngeal muscles will be depended on The position of stimulation location and the specific anatomical structure of patient.For example, the higher people with longer neck may have longer Recurrent laryngeal nerve.Patient's specific template can be developed to consider the particular anatomical difference of patient.

Figure 21-30 illustrates by way of example, and not limitation some selectivitys that can be performed using retardance stimulation is exhausted Fiber stimulating course.Figure 21 illustrates titration nerve stimulation (for example, HALF stimulates) to obtain the process of the Expected Response to stimulating An example.Selective fiber stimulates algorithm to start at 2166.Physiological parameter such as heart rate can be monitored at 2167 As long as and continue executing with selective fiber to stimulate the parameter that algorithm is monitored can be acceptance.When the parameter monitored can not When receiving, nerve stimulation (such as HALF stimulations) is suitably titrated, so as to the nerve stimulation after adjusting again leads to the ginseng of monitoring Number is acceptable.

Figure 22 illustrates an example of the process of checking treatment delivering.Delivery of selective fiber stimulates conduct to control at 2269 A part for treatment.As being generally illustrated at 2270, systems inspection is having checked whether to verify time for the treatment of delivering.It is authenticated Journey can be started by clinician, can be started by patient, or can be automatically activated by the system.Automatic is verified Some embodiments of process may be configured to allow patient to disable proof procedure.If having arrived the time of checking, Ke Yi Temporarily cease at 2271 and exhaust retardance.Also nerve stimulation can be reduced, caused may suffer from when retardance stops with reducing otherwise is exhausted Person is uncomfortable.Patient can be monitored at 2272 to verify that the nerve stimulation still catches neural (for example, " systems inspection ").Example Such as, some embodiments can check laryngeal vibration to confirm vagal stimulation.After proof procedure is completed at 2273, process May return to the stimulation of delivery of selective fiber.Some embodiments enable treatment automatically.

Figure 23 shows an example for raising the process of titration neural stimulation therapy.Different patients may have Different tolerance level to nerve stimulation.Additionally, if the intensity for the treatment of is started with desired intensity level, patient may nothing Method is resistance to treated, but if increasing intensity in the prolonging period of a couple of days or several weeks or time several months, then patient is possible can be more Nerve stimulation is adapted to well and is resistant to treatment.One as treatment can be stimulated using delivery of selective fiber at 2374 Point.As being generally illustrated at 2375, systems inspection is having checked whether time of titration treatment.Titration process can be by clinic Doctor starts, and can be started by patient, or can be automatically activated by the system.Titration process can be performed, wherein, can To stop exhausting retardance stimulation at 2376, and it is incremented by stimulus intensity, then delivers until what patient tolerance increased not having Exhaust the stimulation of retardance.This process can continue, until patient is no longer able to tolerate does not have the stimulation for exhausting retardance, in the time The strength decrease of stimulation can be returned the level that the patient is resistant to and does not exhaust retardance.Can start at 2377 and exhaust retardance And can continue to raise titration process, the strength increase of its moderate stimulation, then deliver until patient tolerance increase with exhausting The stimulation of retardance.The process can continue, until patient is no longer able to tolerate have exhausts the stimulation of retardance, can be by the time The strength decrease of stimulation returns patient and can tolerate and with the level of the stimulation for exhausting retardance.If scalable is strong during treating Degree, then can be configured with these tolerance levels (stimulating with or without retardance is exhausted) setting nerve stimulations strong for system Degree and restriction neural stimulation intensity.

Figure 24 is illustrated for adjusting an example for exhausting the process that retardance stimulates.Can be fine with delivery of selective at 2481 Dimension stimulates the part as treatment, and then whether the process determines that selective fiber stimulates at 2482 and can tolerate.Such as fruit thorniness It can be tolerance to swash, then can store as shown in 2483 and exhaust retardance stimulus parameter and can continue to be incremented by nerve thorn The rise titration process of sharp intensity not can tolerate until the nerve stimulation.If it is not tolerable to stimulate at 2482, The process can be changed at 2484 and exhaust retardance parameter (such as frequency, pulse width and/or amplitude), and determination is accompanied by and repaiies What is changed exhausts stimulus parameter 2485, and whether the stimulation can tolerate.If stimulation is not tolerable 2485, if can be used for repairing Change exhaust retardance stimulate option 2486, then the process may return to 2484 with change exhaust retardance parameter.The process can be with Continuing, until not can be used for further modification the option 2486 that retardance stimulates is exhausted, can now disable and exhaust retardance feature 2487, or until can tolerate 2483 with the nerve stimulation for exhausting retardance and stimulating.At 22483, can store and exhaust retardance thorn The rise titration process of sharp parameter and the intensity for being incremented by nerve stimulation can be continued until that the nerve stimulation not can tolerate.

Figure 25 is illustrated for performing an example for exhausting the process that retardance stimulates.At 2588, it is possible to use first group Stimulus parameter is performed and exhausts retardance stimulation.2589 after the past period, it is possible to use second group of stimulus parameter performs consumption Retardance to the greatest extent stimulates 2590.By way of example, and not limitation, the first group of parameter for stimulating for exhausting retardance can include phase To high frequency (such as 400Hz) to provide quickly retardance, and second group of parameter for being used to exhaust stimulation can include relatively Low frequency (such as 200Hz), to reduce maintaining to exhaust the energy expenditure during retardance stimulates.

Figure 26 illustrates an example for delivering the process of the administration of nerve stimulation.At 2691, system determines whether There is the expected time of the administration for neural stimulation therapy.Administration for neural stimulation therapy can be opened by clinician It is dynamic, can be started by patient, or can be automatically activated by the system.When the time of the administration for being neural stimulation therapy When, the system start-up selective nerve stimulation at 2692, including nerve stimulation and exhaust retardance stimulate.At 2693, it may be determined that Whether the stimulation of desired amount for the administration deliver.If having completed administration, nerve stimulation can be at 2694 Stop, and the process may return to 2691, to wait administration time next time.If administration is not yet completed, nerve thorn Swashing can continue at 2695.

Figure 27 is illustrated for setting nerve stimulation and exhausting an example of the process that retardance stimulates.At 2795, can be with Deliver nerve stimulation and rise titration process (2796 and 2797) can be performed, until reaching desired physiological responses.Can 2798 are stimulated to continue the process to exhaust retardance by delivering.One example of desired physiological responses is that vagus nerve is pierced Sharp desired heart rate or blood pressure response.Desired physiology is not undesirably affected to ring if retardance being exhausted at 2799 and being stimulated Should, then can continue nerve stimulation at 2700.Desired life is undesirably affected if retardance being exhausted at 2799 and being stimulated Reason response, then at 2701 can 2795 and 2796 adjust nerve stimulations, or can adjust exhaust retardance and adjusted Section exhausts retardance and can deliver at 2798.

Figure 28 is shown with of the process of the administration for exhausting retardance stimulus parameter delivering nerve stimulation more than a group Example.Can start at 2802 and exhaust retardance (such as SAHF) and nerve stimulation (for example, HALF).First group of stimulation can be used Parameter is performed and exhausts retardance stimulation.2803 after the past period, it is possible to use first group of stimulus parameter stops consumption Blocking stimulation to the greatest extent, and can exhaust retardance using second group of stimulus parameter execution stimulates 2804.It is unrestriced by example Mode, the first group of parameter stimulated for exhausting retardance can include relatively high frequency (such as 400Hz), to provide quick resistance It is stagnant, and second group of parameter for being used to exhaust stimulation can include relatively low frequency (such as 200Hz) keeping exhausting retardance Energy expenditure is reduced during stimulation.2805, it may be determined whether deliver the stimulation of the desired amount for administration.After It is continuous to stimulate, until completing administration.If completed administration, nerve stimulation and exhaust block stimulation can stop at 2806 Only, and the process may return to 2802 with etc. be ready to use in the initiation being administered next time for the treatment of.

Figure 29 illustrates an example for performing the process of selective nerve stimulation.At 2907, it is possible to use first Group stimulus parameter (such as SAHF₁) perform to exhaust and block stimulation.2908 after the past period, it is possible to use first Group stimulus parameter stops exhausting retardance stimulation, and can use second group of stimulus parameter (such as SAHF₂) perform exhaust retardance Stimulate 2909.By way of example, and not limitation, the first group of parameter for stimulating for exhausting retardance can include relatively high Frequency (such as 400Hz), to provide rapid blocking, and second group of parameter for being used to exhaust stimulation can include relatively low frequency (such as 200Hz), to maintain to reduce energy expenditure during exhausting retardance stimulation.Consumption can started with first group of parameter Start nerve stimulation (for example, HALF) 2910 when blocking to the greatest extent, after retardance is exhausted with first group of parameter startup but can use Second group of parameter is performed to exhaust and start nerve stimulation (for example, HALF) 2910 before retardance, or can be using second group of ginseng Number execution to exhaust and start nerve stimulation (for example, HALF) 2910 after retardance.2911, it may be determined whether deliver for The stimulation of the desired amount of administration.Can continue to stimulate, until completing administration.If having completed administration, nerve stimulation and consumption To the greatest extent retardance stimulation can stop at 2912, and the process may return to 2907 with etc. be ready to use in treatment next time to The initiation of medicine.

Figure 30 shows an example for titrating the process of selective nerve stimulation.3013, the water that can be tolerated Flat delivering is with the neural stimulation therapy for exhausting retardance stimulation.Titration process can be started by clinician, can be opened by patient It is dynamic, or can be automatically activated by the system.3014, if the time of titration, then titration process can be performed Such as raise titration process to determine the new tolerance threshold 3015 of stimulation.The process may return to 3013, so as to corresponding to The setting of the new tolerance threshold for stimulating continues delivery of selective nerve stimulation.Exhausting the target of the titration process of retardance may include With as low as possible (to save battery) while keeping the electric current delivering for exhausting retardance as much as possible to exhaust retardance if necessary.Nerve The target of the titration process of stimulation may include to provide stimulation as much as possible to capture desired aixs cylinder as much as possible, and Extra energy does not cause to avoid excessive energy expenditure in the case that significant amount of extra expectation aixs cylinder is captured.

Illustrate present subject matter with reference to the vagal stimulation for heart failure.However, present subject matter is not It is confined to this.Can be the other treatment execution present invention master for being related to vagal stimulation or the stimulation of other neural targets Topic.The example of this treatment includes, but not limited to for inflammatory disorders such as CrohnShi diseases, rheumatoid arthritiss, many devices Official's nonfunction (i.e. spanish influenza；Large-area burns) vagal stimulation, for epilepsy, depression, eating disorders With the vagal stimulation of pain, for pain and the spinal cord stimulation of heart failure, pressure receptor stimulates, for hypertension Nerve stimulation, peripheral nerve stimulation, for the occipital bone nerve stimulation of migraine, spasm, asthma or chronic obstructive pulmonary disease.

Figure 31-34 is shown suitable for providing the system implementation plan of vagal stimulation, and is shown as that a left side can be stimulated With the vagal bilateral system in the right side.Those those of ordinary skill are readily apparent that, on the basis of reading and understanding present disclosure, The system can be designed as only stimulating right vagus nerve, and the system can be designed as only stimulating left vagus nerve, and should System can be designed as both bilateral stimulation right and left vagus nerves.Additionally, system can be designed as stimulating except neck fan Walk the neural target outside nerve.The system can be designed as stimulating nerve traffic (secondary friendship to be provided when vagus nerve is stimulated Sense neural response), or suppress nerve traffic (providing sympathetic response when vagus nerve is suppressed).Various embodiment deliverings The Unidirectional stimulation or selective stimulating of some nerve fibers in nerve.

Figure 31 shows a system implementation plan, wherein the chest that IMD 3117 is placed in into patient is subcutaneously or intramuscularly Under, it is positioned to stimulate vagus nerve along with (many) lead 3118.According to various embodiments, (many) nerve stimulation lead 3118 can be subcutaneous towards neural target.Some embodiments can have neural card skin (cuff) electrode or screw electrode to pierce Sharp neural target.Some vagal stimulation lead embodiments are input in the blood vessel of neural target by Ink vessel transfusing, and Stimulate neural target through blood vessel (transvascularly) using endovascular (multiple) electrode.For example, some embodiments Using (multiple) the electrode stimulating vagus nerve in internal jugular vein.Other embodiments are to quiet in endotracheal, neck The larynx branch of arteries and veins and the neural target delivering nerve stimulation of subclavian vein.Other neural targets, such as heart god can be stimulated Jing and heart fat pad.The system for illustrating can be included on the shell of equipment without lead ECG electrode 3119.These ECG are electric Pole can be used in for example detecting each several part of heart rate and detection cardiac cycle.

Figure 32 shows the system implementation plan including implantable medical device (IMD) 3217, its have be positioned to stimulate (multiple) satellite electrode (satellite electrode) 3220 of at least one neural target.(multiple) satellite electrode IMD is connected to via wireless link, the IMD serves as the planet of satellite.Can be performed by wireless link is stimulated and is communicated.Nothing The example of wired link includes RF links and ultrasonic link.The example of satellite electrode includes subintegumental electrode, neural cuff electrode and blood Electrode in pipe.The system can include be located at equipment shell on without lead ECG electrode.These ECG electrodes 3219 can be used In each several part for for example detecting heart rate and cardiac cycle.

Figure 33 illustrate according to various embodiments be placed in the chest of patient subcutaneously or intramuscularly under IMD3317, its tool Have (many) lead 3321 be positioned to heart provide CRM treatment, and with (many) lead 3318 be positioned to stimulate and/or Suppress the nerve traffic at neural target such as vagus nerve.According to various embodiments, (many) nerve stimulation lead can be It is subcutaneous towards neural target.Some embodiments can have neural cuff electrode or screw electrode to stimulate neural target.Some Lead embodiment is input in the blood vessel of neural target by Ink vessel transfusing, and is passed through using endovascular (multiple) changer Vascular stimulation neural target.For example, some embodiments can use (multiple) electrode targeting fan in internal jugular vein absent-minded Jing.

Figure 34 illustrates the IMD 3417 according to various embodiments, and there is (many) lead 3421 to be positioned to carry heart for it For CRM treatments, and it is positioned to stimulate and/or suppress neural target such as vagus nerve with satellite transducers 3420.Satellite becomes Parallel operation 3420 operationally communicates via wireless link with IMD, and the IMD serves as the planet of satellite.Wireless link can be passed through Performing stimulates and communicates.The example of wireless link includes RF links and ultrasonic link.Although not shown, but some embodiments Muscle stimulation is performed using wireless link.The example of satellite transducers includes subintegumental electrode, neural cuff electrode and Ink vessel transfusing electricity Pole.

Detailed description above is intended to illustrative and not restrictive.Therefore, it should will with reference to appended right Ask, and the four corner of the entitled equivalent of these claim is determining the scope of the present disclosure.

Claims (29)

1. a kind of system, it includes：

Stimulator, the first aixs cylinder and delivering during the stimulator is configured to deliver nerve stimulation to capture nerve exhausts resistance It is stagnant stimulation to capture nerve in the second aixs cylinder, second group of aixs cylinder is the subset of first group of aixs cylinder, exhaust retardance stimulation include The series of pulses exhausted at pulse frequency between about 100Hz to about 1KHz, and nerve stimulation is included in The series of pulses at boost pulse frequency in the range of 0.25Hz to 50Hz；

With at least one controller, at least one controller is configured to be communicated with stimulator and control exhausts retardance Stimulate and nerve stimulation, at least a portion nerve stimulation and at least a portion exhaust retardance stimulation and be delivered with effectively in delivering Nerve block is provided while nerve stimulation.

2. the system of claim 1, wherein, the stimulator is configured with first electrode and second electrode delivering nerve thorn Swashing nerve, and exhaust retardance using first electrode and second electrode delivering stimulates to nerve.

3. the system of claim 1, wherein the stimulator is configured with first electrode and second electrode delivering nerve thorn Swashing nerve, and exhaust retardance using the 3rd electrode and the delivering of the 4th electrode stimulates nerve to nerve.

4. the system of claim 1, wherein, the stimulator is configured with first electrode and second electrode delivering nerve thorn Swashing nerve, and exhaust retardance using second electrode and the delivering of the 3rd electrode stimulates to nerve.

5. according to the system of any one of aforementioned claim, wherein, the subset for forming first group of second group has than described The low stimulus threshold of first group of remainder.

6. according to the system of any one of aforementioned claim, wherein, the controller is configured to：

Control exhausts retardance stimulation and nerve stimulation to provide with the alternate intermittence for stimulating the ON periods and stimulating OFF period Nerve stimulation；

Stimulating ON periods but not the first aixs cylinder in stimulating OFF period to deliver nerve stimulation to capture nerve；With

Stimulate the ON periods but do not stimulate OFF period delivering to exhaust the second aixs cylinder during retardance stimulates to capture nerve.

7. according to the system of any one of aforementioned claim, wherein, the controller is configured to starting nerve stimulation Start before delivering and exhaust the delivering that retardance stimulates.

8. the system of claim 7, wherein, stimulate the ON periods to be the time period between 1/4 second and 150 seconds, and OFF period is stimulated to be the time period between 1 second and 150 seconds.

9., according to the system of any one of claim 6-8, it also includes the biosensor for being configured to sense physiological parameter, can Be operatively coupled to sensor to detect the controller of the physiological event from the physiological parameter for being sensed, controller further by It is configured to the timing that detected physiological event triggers interval sexual stimuluses.

10. according to the system of any one of aforementioned claim, wherein, nerve stimulator is configured to delivering stimulates absent-minded to fan The neck area of Jing, second group of aixs cylinder includes A type motor fibers.

The system of 11. claim 10, wherein, at least some aixs cylinder in first group of aixs cylinder is Type B fiber, and second Group does not include at least some the Type B fiber in first group.

12. according to the system of any one of claim 1-11, wherein, the controller is configured to perform the titration journey of programming Sequence, and in the titration procedure for performing programming, the controller is configured to interrupt to stimulate nerve delivering, in Interruption period between The following article Adjust nerve stimulation or exhaust stimulate at least one, and recover to nerve delivering stimulate.

The system of 13. claim 12, wherein, adjust nerve stimulation or exhaust stimulate at least one in, controller quilt It is configured at least one for adjusting the amplitude of nerve stimulation or exhausting in the amplitude of stimulation.

14. according to the system of any one of claim 12-13, wherein, in adjusting nerve stimulation or exhausting stimulation at least In one kind, controller is configured to adjust the pulse width of the series of pulses in nerve stimulation or exhausts a succession of in stimulating At least one in the pulse width of pulse.

A kind of 15. methods, it includes：

Nerve delivering with multiple aixs cylinders is stimulated, wherein, delivering stimulation includes：

Delivering is configured to capture the nerve stimulation of first group of aixs cylinder in nerve, wherein, delivering nerve stimulation includes delivering in thorn A succession of electric pulse at sharp pulse frequency, wherein the boost pulse frequency about 0.25Hz and about 50Hz scope it Between, wherein the nerve stimulation for being delivered can induce action potential in first group of aixs cylinder；And

Delivering is configured to capture the presynaptic of second group of aixs cylinder in nerve and exhausts retardance and stimulate, and second group is first group of son Collection, wherein, the delivering presynaptic exhausts retardance stimulation to be included delivering a succession of electric pulse exhausted at pulse frequency, exhausts pulse frequency Rate between about 100Hz to about 1kHz,

Wherein, deliver at least a portion nerve stimulation and at least a portion exhausts retardance and stimulates with effectively in delivering nerve stimulation While nerve block is provided.

The method of 16. claim 15, wherein, the subset for forming first group of second group has the remainder than first group low Stimulus threshold.

17. according to the method for any one of claim 15-16, wherein, delivering nerve stimulation is included with higher than exhausting stimulation Amplitude delivering stimulates.

18. according to the method for any one of claim 15-17, wherein, nerve delivering is stimulated includes that delivering has alternately Stimulate the ON periods and stimulate the intermittent nerve stimulation of OFF period, wherein；

Delivering is configured to capture the nerve stimulation of first group of aixs cylinder in nerve and is included in the stimulation ON periods but not when OFF is stimulated Section delivers a succession of electric pulse with boost pulse frequency；With

The delivering presynaptic exhausts retardance stimulation and is included in the stimulation ON periods but is not stimulating OFF period to exhaust pulse frequency delivering A succession of electric pulse.

19. according to the method for any one of claim 15-18, wherein, the delivering presynaptic exhausts retardance and delivers nerve stimulation It is included in before the delivering for starting nerve stimulation and starts the presynaptic and exhaust the delivering of retardance.

20. according to the method for any one of claim 18-19, wherein, stimulate the ON periods to be between 1/4 second and 150 seconds In the range of time period, and stimulate OFF period to be time period between 1 second and 150 seconds.

21. according to the method for any one of claim 18-20, wherein, the intermittent nerve stimulation of delivering includes sensing physiology ginseng The physiological event from the physiological parameter for being sensed is counted and detects, and based on the detected intermittent god of physiological event triggering The timing that Jing stimulates.

22. according to the method for any one of claim 15-21, wherein, nerve delivering stimulation is included to vagal neck Portion's regional delivery stimulates, and second group of aixs cylinder includes A type motor fibers.

The method of 23. claim 22, wherein, at least some aixs cylinder in first group of aixs cylinder is Type B fiber, and second At least some Type B fiber that group includes not included in first group.

24. according to the method for any one of claim 15-23, wherein, delivering nerve stimulation includes using first electrode and the Two electrodes deliver nerve stimulation, and delivering exhausts stimulation and includes exhausting stimulation using first electrode and second electrode delivering.

25. according to the method for any one of claim 15-23, wherein, delivering nerve stimulation includes using first electrode and the Two electrodes deliver nerve stimulation, and delivering exhausts stimulation and includes exhausting stimulation using the 3rd electrode and the delivering of the 4th electrode.

26. according to the method for any one of claim 15-23, wherein, delivering nerve stimulation includes using first electrode and the Two electrodes deliver nerve stimulation, and delivering exhausts stimulation and includes exhausting stimulation using second electrode and the delivering of the 3rd electrode.

27. according to the method for any one of claim 15-26, and it further includes to perform titration procedure, wherein, perform titration Program includes：

Interrupting stimulates nerve delivering；

Interruption period between The following article adjust nerve stimulation or exhaust stimulate at least one；And

Recover to stimulate nerve delivering.

The method of 28. claim 27, wherein, at least one for adjusting nerve stimulation or exhausting in stimulating includes adjusting nerve thorn Sharp amplitude or at least one in exhausting the amplitude of stimulation.

29. according to the method for any one of claim 27-28, wherein, adjust nerve stimulation or exhaust in stimulating at least one Kind include adjusting the pulse width of the series of pulses in nerve stimulation or exhaust the pulse width of series of pulses in stimulation In at least one.